Starting materials for the production of solid dosage forms for drugs generally are in the form of powders. In the conventional processing mode, these powders are mixed thoroughly to achieve homogeneity and the resulting mixture is filled into capsules or compressed into tablets either directly or after granulation. Obtaining suitable product requires multiple auxiliary ingredients such as diluents, binders, lubricants, glidants, disintegrands, and stabilizers. Furthermore, auxiliary ingredients must be specifically formulated in correct proportions adapted to the particular drug and processing equipment. These prior art methods are well suited for batch production. However, continuous production methods present issues not addressed by methods used for batch production. Furthermore, batch production is slower, less economical and requires intermittent sampling to maintain quality control, since it is not possible to test every tablet for the correct amount of ingredients.
Conventional batch methods can be used for almost all drugs with satisfactory results. However, specific instances allow the use of more economical approaches. Using the methods of the instant invention, it is possible to administer many drugs in the form of water-soluble inclusion complexes and use a simpler, continuous production process.
Cyclodextrins are a group of compounds consisting of or derived from the three parent cyclodextrins: alpha- beta- and gamma-cyclodextrins. Parent cyclodextrins are often chemically derivatized to improve their properties. Examples of such derivatives include partial methyl, hydroxypropyl or sulfoalkyl ethers, or partial acetyl esters of parent cyclodextrins. Cyclodextrins have numerous uses based on their ability to solubilize chemicals through formation of complexes, which are of inclusion type and form spontaneously. Some cyclodextrins by themselves can form films, but are not gel forming agents.
Cyclodextrin complexes of drugs dissolve rapidly in water and, consequently, are especially well suited for administration of drugs that should be absorbed from the mouth cavity. Drugs absorbed from the mouth cavity directly enter blood circulation, whereas drugs absorbed from the rest of the gastrointestinal tract enter blood circulation only after passage through the liver, where many drugs are destroyed. This was exemplified by administration of cyclodextrin complexes of sex hormones in U.S. Pat. No. 4,596,795. Data in that patent showed that, when a hormone was absorbed from the mouth, it entered into blood circulation rapidly and efficiently, while when absorbed from the stomach, only a small amount slowly entered the blood stream. Drugs in appropriate carriers that are absorbed from the mouth have the potential to replace compositions for parenteral administration (i.e., injections) for use where rapid effects are required (e.g., migraine headaches). For desired absorption to occur effectively, it is critical that the cyclodextrin:drug inclusion complex be in direct contact with the oral mucosa; then, the drug (and not cyclodextrin) is absorbed. Furthermore, the drug is not swallowed and absorption occurs through the mucous membrane of mouth directly into the blood stream. For convenience, it is important that total time of administration is brief. In previous art (U.S. Pat. No. 4,596,795 and clinical studies based on this patent including C. A. Stuenkel et al., Journal of Clinical Endocrinology and Metabolism, 72, 1054-1059, 1991; E. Salehian et al., ibid, 80, 3567-3575, 1995; H. Fridriksdottir et al., Pharmazie, 51, 39-42, 1996) conventional tablets containing cyclodextrin complexes of sex hormones were used; that is, ingredients were in the form of powders.
Regarding prior art, the following publications direct to solid dosage forms different from conventional tablets. Historical formulations predating tablets include medicated papers. These were blotting papers soaked in solution of a medicinal (e.g., iodine), dried, and used by pressing directly against the skin or mucosal surface. Medicated papers were in universal use at the beginning of the twentieth century (D. Hunter: Papermaking, Dover Publishers, Inc., 1974). Presently, other forms have almost completely replaced them.
In U.S. Pat. No. 4,349,531, solid pharmaceutical forms on laminates of webs or on paper compositions are described. In these forms, the medication is deposited on surfaces of these webs in fine particulate form, that is, not dissolved. Similar webs are described in U.S. Pat. No. 4,180,558, improved by making them from carboxymethylcellulose paper. Use of that type of paper prevents layers from sticking together when the solid dosage must be made of stacks of paper to carry the amount of drug to be administered.
In U.S. Pat. No. 5,629,003, a dosage form containing an active ingredient, film-formers, gel-formers and fillers was extruded and dried either alone or spread onto nonabsorbing carrying paper from which it could be released. The dosage itself is specified to be rapidly disintegrating. Cyclodextrins in that patent are listed as fillers with emphasis that they are present in the product in substantially undissolved form (page 9) and not specified to form inclusion complexes. A gel-forming agent is declared necessary.
There is art teaching cyclodextrins are permanently bound to cellulose or cellulose based materials by chemical bonds. The medicinal is complexed to such immobilized cyclodextrins; for example, Hungarian Patent 54,506. Upon moistening such a composite, only the medicinal, and not the cyclodextrin, is released. Thus, there is no carrier that can carry the medicinal to its absorption site. Release of medicinal (and the following absorption into tissue) is consequently a slow process. In the case of the instant invention, the cyclodextrin is not permanently bound to the cellulosic material.